Petros Isaakidis

Ambulatory Multi-Drug Resistant Tuberculosis Treatment Outcomes in a Cohort of HIV-Infected Patients in a Slum Setting in Mumbai, India

Background India carries one quarter of the global burden of multi-drug resistant TB (MDR-TB) and has an estimated 2.5 million people living with HIV. Despite this reality, provision of treatment for MDR-TB is extremely limited, particularly for HIV-infected individuals. Médecins Sans Frontières (MSF) has been treating HIV-infected MDR-TB patients in Mumbai since May 2007. This is the first report of treatment outcomes among HIV-infected MDR-TB patients in India. Methods HIV-infected patients with suspected MDR-TB were referred to the MSF-clinic by public Antiretroviral Therapy (ART) Centers or by a network of community non-governmental organizations. Patients were initiated on either empiric or individualized second-line TB-treatment as per WHO recommendations. MDR-TB treatment was given on an ambulatory basis and under directly observed therapy using a decentralized network of providers. Patients not already receiving ART were started on treatment within two months of initiating MDR-TB treatment. Results Between May 2007 and May 2011, 71 HIV-infected patients were suspected to have MDR-TB, and 58 were initiated on treatment. MDR-TB was confirmed in 45 (78%), of which 18 (40%) were resistant to ofloxacin. Final treatment outcomes were available for 23 patients; 11 (48%) were successfully treated, 4 (17%) died, 6 (26%) defaulted, and 2 (9%) failed treatment. Overall, among 58 patients on treatment, 13 (22%) were successfully treated, 13 (22%) died, 7 (12%) defaulted, two (3%) failed treatment, and 23 (40%) were alive and still on treatment at the end of the observation period. Twenty-six patients (45%) experienced moderate to severe adverse events, requiring modification of the regimen in 12 (20%). Overall, 20 (28%) of the 71 patients with MDR-TB died, including 7 not initiated on treatment. Conclusions Despite high fluoroquinolone resistance and extensive prior second-line treatment, encouraging results are being achieved in an ambulatory MDR-T- program in a slum setting in India. Rapid scale-up of both ART and second-line treatment for MDR-TB is needed to ensure survival of co-infected patients and mitigate this growing epidemic.

Adverse Events among HIV/MDR-TB Co-Infected Patients Receiving Antiretroviral and Second Line Anti-TB Treatment in Mumbai, India

Background Significant adverse events (AE) have been reported in patients receiving medications for multidrug- and extensively-drug-resistant tuberculosis (MDR-TB & XDR-TB). However, there is little prospective data on AE in MDR- or XDR-TB/HIV co-infected patients on antituberculosis and antiretroviral therapy (ART) in programmatic settings. Methods Médecins Sans Frontières (MSF) is supporting a community-based treatment program for drug-resistant tuberculosis in HIV-infected patients in a slum setting in Mumbai, India since 2007. Patients are being treated for both diseases and the management of AE is done on an outpatient basis whenever possible. Prospective data were analysed to determine the occurrence and nature of AE. Results Between May 2007 and September 2011, 67 HIV/MDR-TB co-infected patients were being treated with anti-TB treatment and ART; 43.3% were female, median age was 35.5 years (Interquartile Range: 30.5–42) and the median duration of anti-TB treatment was 10 months (range 0.5–30). Overall, AE were common in this cohort: 71%, 63% and 40% of patients experienced one or more mild, moderate or severe AE, respectively. However, they were rarely life-threatening or debilitating. AE occurring most frequently included gastrointestinal symptoms (45% of patients), peripheral neuropathy (38%), hypothyroidism (32%), psychiatric symptoms (29%) and hypokalaemia (23%). Eleven patients were hospitalized for AE and one or more suspect drugs had to be permanently discontinued in 27 (40%). No AE led to indefinite suspension of an entire MDR-TB or ART regimen. Conclusions AE occurred frequently in this Mumbai HIV/MDR-TB cohort but not more frequently than in non-HIV patients on similar anti-TB treatment. Most AE can be successfully managed on an outpatient basis through a community-based treatment program, even in a resource-limited setting. Concerns about severe AE in the management of co-infected patients are justified, however, they should not cause delays in the urgently needed rapid scale-up of antiretroviral therapy and second-line anti-TB treatment.

Excellent outcomes among HIV+ children on ART, but unacceptably high pre-ART mortality and losses to follow-up: a cohort study from Cambodia

BackgroundAlthough HIV program evaluations focusing on mortality on ART provide important evidence on treatment effectiveness, they do not asses overall HIV program performance because they exclude patients who are eligible but not started on ART for whatever reason. The objective of this study was to measure mortality that occurs both pre-ART and during ART among HIV-positive children enrolled in two HIV-programs in Cambodia.MethodsRetrospective cohort study on 1168 HIV-positive children <15 years old registered in two HIV-programs over a four-year period. Mortality rates were calculated for both children on treatment and children not started on ART.ResultsOver half (53%) of children were 5 years or above and only 69(6%) were <18 months. Overall, 9% (105/1168) of children died since the set-up of the programs. By the end of the observation period, 66(14.5%) patients not on ART had died compared to 39(5.5%) of those under treatment, and 100(22%) who did not start ART were lost-to-follow-up compared to13(2%) on ART. 66/105 (62.8%) of all in-program deaths occurred before starting ART, of which 56% (37/66) and 79% (52/66) occurred within 3 and 6 months of enrolment respectively. Mortality rate ratio between children not on ART and children on ART was 4.1 (95%CI: 2.7–6.2) (P < 0.001). The most common contributing cause of death in first 3 months of treatment and in first 3 months of program enrollment was tuberculosis. 41/52 (79%) children who died within 6 months of enrollment had met the ART eligibility criteria before death.ConclusionHIV-positive children experienced a high mortality and loss-to-follow-up rates before starting ART. These program outcomes may be improved by a more timely ART initiation. Measuring overall in-program mortality as opposed to only mortality on ART is recommended in order to more accurately evaluate pediatric HIV-programs performance.

Serogroup X in meningococcal disease, Western Kenya.

To the Editor: Although >12 different serogroups of Neisseria meningitidis exist, most disease outbreaks across the African meningitis epidemic belt are caused by serogroup A and, less frequently, by serogroups C and W135 (1). N. meningitidis serogroup X was first described in the 1960s and has been found to cause a few cases of invasive disease across North America, Europe, and Africa (2). In Africa, small serogroup X outbreaks have been described in Ghana (9 cases over a 2-year period) and in Niger (134 cases between 1995 and 2000) (3,4). In 2006, however, 51% of 1,139 confirmed cases of meningococcal meningitis in Niger were found to be caused by serogroup X (5). Before the 2005-06 meningococcal epidemic season, no published reports had described serogroup X isolates in East Africa. We report the involvement of N. meningitidis serogroup X in an outbreak of meningococcal disease in Western Kenya. In January 2006, the Ministry of Health of Kenya and Medecins sans Frontieres were notified of a suspected meningococcal disease outbreak in West Pokot District, bordering Uganda, in Western Kenya. On the basis of the initial outbreak investigation, the outbreak was assessed to have begun in late December 2005. Subsequent active surveillance, using the same clinical case definition of sudden fever onset with stiff neck, altered mental status, or both, showed 74 suspected cases through mid-March 2006, with a case-fatality rate of 20%. No cases were reported after March 2006. Over the course of the outbreak, cerebrospinal fluid samples were obtained from 18 patients. Due to low population density, poor access to seminomadic populations, and the limited nature of the outbreak (relatively small numbers dispersed over a wide geographic region), obtaining specimens from untreated patients in West Pokot proved difficult. Three of the 5 first samples were found to show gram-negative diplococci on staining, the next 2 were negative on Pastorex rapid latex agglutination test (Bio-Rad Laboratories, Hercules, CA, USA) (during the outbreak investigation), and a subsequent 13 were sent to the African Medical and Research Foundation (AMREF) laboratory in Nairobi, Kenya, for culture and susceptibility testing. From these 13 specimens, 2 yielded a pure growth of N. meningitidis serogroup X, while no growth was observed for the remaining 11 specimens. These 2 cultures were subsequently confirmed as serogroup X by the World Health Organization Collaborating Centre for Meningococci in Oslo, Norway. Multilocus sequence typing and sequencing of the porA and fetA genes as described (http://pubmlst.org/neisseria/), showed that the infecting strain belonged to a new sequence type, ST-5403, and that it was subtype P1.19,26 and FetA type F3-27. This sequence type is unrelated to other serogroup X isolates from Africa, including those from the latest serogroup X outbreak in Niger, but it resembles a sequence type isolated in the United States in the 1970s. In addition to the testing at AMREF and in the Oslo laboratory, the 13 samples were also analyzed by PCR at the US Naval Medical Research Unit No. 3 in Cairo, Egypt. Overall, 5 of these 13 specimens were positive for serogroup X (including the 2 samples found to be serogroup X at AMREF and confirmed by PCR in Oslo) and 1 each was positive for serogroups C, W135, and Y. At the same time as this outbreak in Western Kenya, a meningococcal meningitis outbreak was being monitored across the border in the Karamoja region of northeastern Uganda. Seminomadic populations move freely across the 2 countries, and we can assume that there was 1 meningitis outbreak that started in eastern Uganda and spread to Western Kenya. Although initial laboratory testing in Uganda suggested the presence of serogroup A, among 23 specimens subsequently sent to the Oslo laboratory, 11 were identified as serogroup X by PCR and 3 were serogroup W135 (6). Therefore, the outbreaks in both Kenya and Uganda involved multiple N. meningitidis serogroups. In West Pokot, Kenya, the Ministry of Health and Medecins sans Frontieres conducted a vaccination campaign using the trivalent polysaccharide vaccine against serogroups A, C, and W135. Before 2006, previous disease outbreaks caused by serogroup X had not reached the magnitude of those caused by serogroups A, C, or W135; they tended to evolve independently of the occurrence of both serogroups A and C and to be self-limited (3,4). Although most of Kenya is not included in the African meningitis belt, large epidemics of meningococcal disease have been reported previously (7). In conclusion, we would like to highlight the presence of N. meningitidis serogroup X in East Africa, its potential involvement in disease outbreaks, and the difficulties it may cause for laboratory confirmation and, consequently, for making an appropriate epidemic response.

High survival and treatment success sustained after two and three years of first-line ART for children in Cambodia

BackgroundLong-term outcomes of antiretroviral therapy (ART) in children remain poorly documented in resource-limited settings. The objective of this study was to assess two-and three-year survival, CD4 evolution and virological response among children on ART in a programmatic setting in Cambodia.MethodsChildren treated with first-line ART for at least 24 months were assessed with viral load testing and genotyping. We used Kaplan-Meier analysis for survival and Cox regression to identify risk factors associated with treatment failure.ResultsOf 1168 registered HIV-positive children, 670 (57%) started ART between January 2003 and December 2007. Survival probability was 0.93 (95% CI: 0.91-0.95) and 0.91 (95% CI: 0.88-0.93) at 24 and 36 months after ART initiation, respectively. Median CD4 gain for children aged over five years was 704 cells/mm3 at 24 months and 737 at 36 months. Median CD4 percentage gain for children under five years old was 15.2% at 24 months and 15% at 36 months. One hundred and thirty children completed at least 24 months of ART, and 138 completed 36 months: 128 out of 268 (48%) were female. Median age at ART initiation was six years.Overall, 22 children had viral loads of >1000 copies/ml (success ratio = 86% on intention-to-treat-analysis) and 21 of 21 presented mutations conferring resistance mostly to lamivudine and non-nucleoside reverse transcriptase inhibitors. Risk factors for failure after 24 and 36 months were CD4 counts below the threshold for severe immunosupression at those months respectively. Only two out of 22 children with viral loads of >1000 copies/ml met the World Health Organization immunological criteria for failure (sensitivity = 0.1).ConclusionsGood survival, immunological restoration and viral suppression can be sustained after two to three years of ART among children in resource-constrained settings. Increased access to routine virological measurements is needed for timely diagnosis of treatment failure.

Poor Outcomes in a Cohort of HIV-Infected Adolescents Undergoing Treatment for Multidrug-Resistant Tuberculosis in Mumbai, India

Background Little is known about the treatment of multidrug-resistant tuberculosis (MDR-TB) in HIV-co-infected adolescents. This study aimed to present the intermediate outcomes of HIV-infected adolescents aged 10–19 years receiving second-line anti-TB treatment in a Médecins Sans Frontières (MSF) project in Mumbai, India. Methods A retrospective review of medical records of 11 adolescents enrolled between July 2007 and January 2013 was undertaken. Patients were initiated on either empirical or individualized second-line ambulatory anti-TB treatment under direct observation. Results The median age was 16 (IQR 14–18) years and 54% were female. Five (46%) adolescents had pulmonary TB (PTB), two (18%) extrapulmonary disease (EPTB) and four (36%) had both. Median CD4 count at the time of MDR-TB diagnosis was 162.7 cells/µl (IQR: 84.8–250.5). By January 2013, eight patients had final and 3 had interim outcomes. Favourable results were seen in four (36.5%) patients: one was cured and three were still on treatment with negative culture results. Seven patients (64%) had poor outcomes: four (36.5%) died and three (27%) defaulted. Three of the patients who died never started on antiretroviral and/or TB treatment and one died 16 days after treatment initiation. Two of the defaulted died soon after default. All patients (100%) on-treatment experienced adverse events (AEs): two required permanent discontinuation of the culprit drug and two were hospitalized due to AEs. No patient required permanent discontinuation of the entire second-line TB or antiretroviral regimens. Conclusions Early mortality and mortality after default were the most common reasons for poor outcomes in this study. Early mortality suggests the need for rapid diagnosis and prompt treatment initiation, and adolescents might benefit from active contact-tracing and immediate referral. Default occurred at different times, suggesting the need for continuous, intensified and individualized psychosocial support for co-infected adolescents. Operational research among co-infected adolescents will be especially important in designing effective interventions for this vulnerable group.

Alarming Levels of Drug-Resistant Tuberculosis in HIV-Infected Patients in Metropolitan Mumbai, India

Background Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India. Methods A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases. Results Between March 2013 and January 2014, ART-center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%–40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR-TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models. Conclusion The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing transmission in the community and health facilities. These data highlight the need to promptly diagnose drug-resistance among all HIV-infected patients by systematically offering access to first and second-line DST to all patients with ‘presumptive TB’ rather than ‘presumptive DR-TB’ and tailor the treatment regimen based on the resistance patterns.

Treating 4,000 diabetic patients in Cambodia, a high-prevalence but resource-limited setting: a 5-year study.

BackgroundDespite the worldwide increasing burden of diabetes, there has been no corresponding scale-up of treatment in developing countries and limited evidence of program effectiveness. In 2002, in collaboration with the Ministry of Health of Cambodia, Médecins Sans Frontières initiated an outpatient program of subsidized diabetic care in two hospital-based chronic disease clinics in rural settings. We aimed to describe the outcomes of newly and previously diagnosed diabetic patients enrolled from 2002 to 2008.MethodsWe calculated the mean and proportion of patients who met the recommended treatment targets, and the drop from baseline values for random blood glucose (RBG), hemoglobin A1c (HbA1c), blood pressure (BP), and body mass index (BMI) at regular intervals. Analysis was restricted to patients not lost to follow-up. We used the t test to compare baseline and subsequent paired values.ResultsOf 4404 patients enrolled, 2,872 (65%) were still in care at the time of the study, 24 (0.5%) had died, and 1,508 (34%) were lost tofollow-up. Median age was 53 years, 2,905 (66%) were female and 4,350 (99%) had type 2 diabetes. Median (interquartile range (IQR)) follow-up was 20 months (5 to 39.5 months). A total of 24% (51/210) of patients had a HbA1c concentration of <7% and 35% (709/1,995) had a RBG <145 mg/dl within 1 year. There was a significant drop of 109 mg/dl (95% confidence interval (CI) 103.1 to 114.3) in mean RBG (P < 0.001) and a drop of 2.7% (95% CI 2.3 to 3.0) in mean HbA1c (P < 0.001) between baseline and month 6. In all, 45% (327/723) and 62% (373/605) of patients with systolic or diastolic hypertension at baseline, respectively, reached = 130/80 mm Hg within 1 year. There was a drop of 13.5 mm Hg (95% CI 12.1 to 14.9) in mean systolic blood pressure (SBP) (P < 0.001), and a drop of 11.7 mm Hg (95% CI 10.8 to 12.6) in mean diastolic blood pressure (DBP) (P < 0.001) between baseline and month 6. Only 22% (90/401) patients with obesity at baseline lowered their BMI <27.5 kg/m2 after 1 year. Factors associated with loss to follow-up were male sex, age >60 years, living outside the province, normal BMI on admission, high RBG on last visit, and coming late for the last consultation.ConclusionSignificant and clinically important improvements in glycemia and BP were observed, but a relatively low proportion of diabetic patients reached treatment targets. These results and the high loss to follow-up rate highlight the challenges of delivering diabetic care in rural, resource-limited settings.

Combination Treatment for Visceral Leishmaniasis Patients Coinfected with Human Immunodeficiency Virus in India.

We describe the safety and efficacy of treating visceral leishmaniasis (VL) in patients with human immunodeficiency virus-VL coinfection with concurrent intravenous liposomal amphotericin B (AmBisome) and oral miltefosine (Impavido) in India. The regimen was safe, well tolerated, with lower relapse rates than monotherapy.

Evaluation of a systematic substitution of zidovudine for stavudine-based HAART in a program setting in rural Cambodia.

Objective:To evaluate a treatment strategy of substituting zidovudine (ZDV) for stavudine (d4T)-based highly active antiretroviral therapy (HAART), aimed at preventing d4T-associated toxicity, in a programmatic setting in rural Cambodia. Methods:Survival probability, CD4 gain, anemia incidence, and factors associated with severe anemia were analyzed in a cohort of adult patients switched from d4T- to ZDV-containing regimens from March 2006 to March 2007. Results:Among 527 patients systematically switched to ZDV after d4T-based HAART for a median of 18 months, 4 (0.8%) patients died, 2 (0.4%) were lost to follow-up, 18 (3.4%) were transferred out, and 503 (95.4%) remained on HAART. Median CD4 gain was +263.5 cells/μL (interquartile range: 89.25-369.5) at 24 months. Within 1 year after the switch, 21.9% and 7.1% of patients developed anemia (grades 1-4) and severe anemia (grades 3-4), respectively. Low body mass index (≤18) and low CD4 count (<200 cells/μL) at the time of switch were factors associated with severe anemia. Additional follow-up visits for laboratory monitoring and adherence counseling, increased absenteeism from work, and transportation costs for the patients were noted. Conclusions:The switch strategy of substituting ZDV for d4T-based HAART led to satisfactory overall clinical outcomes. However, it resulted in a relatively high incidence of mild to severe anemia and increased burden for the program and the patients.